Bacteraemia Caused by Gram-Negative Bacteria, Bloodstream Infection, Febrile Neutropenia (FN), Gram Negative Infections
Conditions
Keywords
Antibiotics, Bloodstream Infection, Hematological patients with febrile neutropenia, Gram-negative
Brief summary
The goal of this clinical trial is to learn if a personalized duration of antibiotic therapy, based on clinical stability, is as effective as a standard duration of at least 10 days in hospitalized patients with hematologic malignancies (such as leukemia or lymphoma) who develop febrile neutropenia and Gram-negative bacteraemia. The main questions it aims to answer are: * Can a personalized antibiotic duration increase the number of days free from anti-Gram-negative therapy within 28 days without compromising patient safety? * How does the duration of antibiotic therapy (short vs. prolonged) affect the rate and modality of gut microbiota reconstitution? Researchers will compare: * Group A (Personalized Duration): Antibiotics are stopped after the patient maintains clinical stability (no fever and stable vital signs) for 72 consecutive hours. * Group B (Standard of Care): Antibiotics are continued for a standard duration, typically at least 10 days, based on current clinical surveys and physician decision. Participants will: * Be randomized to receive either the personalized or the standard duration of antibiotic therapy once a Gram-negative infection is confirmed in the blood. * Be monitored for 28 days to assess for new fever episodes, recurrence of infection, and overall survival. * If participating in the microbiological sub-study, provide biological samples (blood, feces, and rectal swabs) at specific time points (at the onset of fever, at the end of treatment, and at day 28). * Undergo specialized laboratory testing (Whole Metagenomic Sequencing) on the collected samples to evaluate the evolution of their intestinal and blood microbiota and the presence of antibiotic-resistant genes.
Detailed description
This is a multicenter, open-label, randomized controlled trial. Upon confirmation of Gram-negative bacteraemia, eligible patients are randomized 1:1 to one of two treatment strategies: * Experimental Arm (Personalized Duration): Antibiotic therapy is discontinued once the patient achieves and maintains clinical stability for 72 consecutive hours. Clinical stability is defined as apyrexia (Tc \< 38°C) for at least 48 hours and a stable or improving qSOFA score. * Control Arm (Standard of Care): Antibiotic therapy duration follows local clinical practice, with a suggested minimum duration of 10 days, consistent with current European and Asian hematological guidelines. In parallel, a prospective observational microbiological sub-study will utilize Shotgun Metagenomic Next-Generation Sequencing (mNGS) to analyze the evolution of the intestinal and blood microbiota. The goal is to compare the rate of MDR organism colonization and the reconstitution of the healthy microbiome between the two antibiotic duration strategies. All participants will undergo clinical monitoring until day 28. For those enrolled in the sub-study, biological samples (stool, rectal swabs, and blood) will be collected at baseline (V1), at the end of treatment (V4), and at the end of the study (V5). These samples will be analyzed to identify clinically significant bacteria and antibiotic-resistance genes.
Interventions
OTHERClinical Stability-Driven Antibiotic Discontinuation Strategy
A therapeutic strategy where the duration of antibiotic treatment for Gram-negative bacteraemia is determined by the achievement of clinical stability (defined as apyrexia for 48h and stable/improved qSOFA score) maintained for 72 consecutive hours
OTHERStandard of Care Antibiotic Duration
This intervention follows the standard clinical practice for treating Gram-negative bacteraemia in hematological patients. The duration of therapy is not fixed by a stability-driven rule but is based on the treating physician's decision, with a suggested minimum of 10 days.
Sponsors
Valeria Cento
Ministry of education, university and research, Italy
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with a hematologic malignancy that is candidate for treatment with chemotherapy or bone marrow transplantation or chimeric antigen receptor T cell therapy (CAR-T) * Diagnosis of febrile neutropenia defined according to the guidelines of the Infectious Disease Society of America, IDSA; ref: Freifeld, A.G., et al., Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis, 2011. 52(4): p. e56-93.) as: Fever: single record of oral temperature \>=38.3°C or a temperature \>=38.0°C sustained over a period of one hour; Neutropenia: absolute neutrophil count \< 1000 cells/microL; Expected duration of neutropenia \>= 7 days * Diagnosis of bacteraemia defined by positive blood cultures (at least 1 vial positive for a non-contaminating microorganism) * Isolation of Gram-Negative species
Exclusion criteria
* Contextual diagnosis of pneumonia * Contextual diagnosis of intra-abdominal infection, in particular: neutropenic enterocolitis/typhlitis or biliary tract infection * Persistently positive blood cultures at randomization * Any condition that endangers the safety of the patient based on the judgment of the treating physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days Free from Anti-Gram-Negative Antibiotic Therapy within 28 days | From the date of index blood culture collection (Day 0) up to Day 28 | Number of days that the participant is alive and free from any anti-Gram-negative antibiotic therapy, calculated from the date of the index blood culture collection (onset of infection) up to Day 28. Antibiotics active exclusively on Gram-positive bacteria (e.g., glycopeptides, daptomycin) and fluoroquinolone prophylaxis are excluded from this calculation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of New Fever Episodes | From the end of antibiotic therapy up to Day 28 | Number of participants experiencing a new episode of fever (Tc ≥ 38.3°C) occurring after a period of apyrexia of at least 72 hours |
| 28-day All-cause Mortality | Up to Day 28 | Number of participants who died from any cause within 28 days from the onset of the index infection (date of first positive blood culture) |
| Relapse of Bloodstream Infection (BSI) by the Same Pathogen | From the end of antibiotic therapy up to Day 28 | Number of participants with a new positive blood culture for the same Gram-negative pathogen identified in the index episode |
| Recurrent BSI by Gram-negative Bacteria | From the end of antibiotic therapy up to Day 28 | Number of participants experiencing a new episode of bloodstream infection caused by any Gram-negative bacteria different from the index pathogen |
| Emergence of Multi-Drug Resistant Organisms (MDRO) | Within 90 days from the index blood culture collection | Number of participants with isolation of a new MDRO from recurrent positive blood cultures, or evidence of a worsened resistance profile compared to the index isolate |
| Incidence of Clostridioides difficile Infection (CDI) | Up to Day 28 | Number of participants with a laboratory-confirmed diagnosis of Clostridioides difficile infection |
| Incidence of Antibiotic-Related Adverse Events | Up to Day 28 | Number of participants experiencing adverse events (AE) judged by the investigator to be related to the antibiotic therapy (e.g., allergic reactions, renal toxicity) |
Countries
Italy
Contacts
CONTACTValeria Cento, MD, PhD
CONTACTMichele Bartoletti, MD, PhD
PRINCIPAL_INVESTIGATORValeria Cento, MD, PhD
Humanitas University
Outcome results
None listed